Difunctionalized aromatic compounds and polymers therefrom

ABSTRACT

The present invention relates to compounds of formula I, which are difunctionalized aromatic compounds, and polymers formed from the same. 
       [R′—(X) a —OC(O)] p —Ar—[NR′—(Y) b —R′] q   I
 
     Polymers formed from the difunctionalized aromatics are expected to have controllable degradation profiles, enabling them to release an active component over a desired time range. The polymers are also expected to be useful in a variety of medical applications.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application claims priority benefit under 35 U.S.C. §119(e)of U.S. Provisional Patent Application Ser. No. 60/741,158 filed Dec. 1,2005. The disclosure this application is incorporated herein byreference.

FIELD OF THE INVENTION

The present invention relates to the discovery of difunctionalizedaromatic compounds and polymers derived therefrom, which can havecontrollable degradation profiles.

BACKGROUND OF THE INVENTION

Polymers prepared from the aromatic compounds, such as terephthalicacid, p-aminobenzoic acid, and p-phenylenediamine exhibit excellentphysical properties, but the polymers are not biodegradable. Polyestersderived from terephthalic acid, such as polyethylene terephthalate(PET), polytrimethylene terephthalate (PTT), and poly(1,4-butyleneterephthalate) (PBT) are used extensively for making fibers and moldingarticles. Some of these are polymers that are used in biomedicalapplications such as non-absorbable surgical sutures, and these polymersare considered to be safe and biocompatible. Unfortunately, thesepolymers are non-absorbable and, therefore, cannot be used as absorbablesutures or as absorbable polymers for the controlled release of drugs.

Due to the availability and numerous uses of the polymers derived fromthese aromatic compounds, it is desirable to enhance their value, forexample, by functionalizing these aromatic compounds and preparingabsorbable polymers therefrom. The resulting absorbable polymers shouldhave a specific controlled degradation profile or range enablingcontrolled release of drugs over an extended, controllable time rangewhen physically admixed with these polymers.

Synthetic absorbable polymers have been used to produce various surgicalproducts such as sutures, implants, prostheses, and the like, forseveral years. Illustrative U.S. patents describing such polymersinclude U.S. Pat. Nos. 3,297,033; 3,044,942; 3,371,069; 3,531,561;3,636,956; Reissue Pat. No. 30,170; and, U.S. Pat. No. 4,052,988.

Implantable surgical devices must be sterile prior to implanting in thebody. Sterilization of devices is usually accomplished by the use ofheat, ethylene oxide, or gamma radiation using a ⁶⁰Co source. In manycases, the use of gamma radiation is the most convenient and mostcertain way to effect sterilization. However, all of the syntheticabsorbable polymers now in commercial use are significantly degraded bygamma radiation. Therefore, unless for some reason degradation of thepolymer is desired (for instance, to greatly accelerate the absorptionrate), the use of gamma radiation is precluded for the purpose ofsterilizing the presently commercial synthetic absorbable polymers.

This invention also provides a new class of polymers that are absorbableand which are expected to be sterilizable by gamma radiation while stillretaining a desirable level of physical and biological properties.

SUMMARY OF INVENTION

The present invention provides novel difunctionalized aromaticcompounds, which are hydrolysable and can be useful for medicalapplications (e.g., drug delivery and solvents for dissolving drugs).

The present invention also provides novel, absorbable polymers andco-polymers (e.g., polyesters, polyamides, polyester amides,polyurethanes, and polyanhydrides) derived from the difunctionalizedaromatic compounds. These polymers are expected to have controllabledegradation profiles.

The present invention also provides novel medical devices comprisingdifunctionalized aromatic compounds or polymers derived therefrom.

This invention also provides a new class of polymers that are absorbableand that are expected to be sterilizable by gamma radiation while stillretaining a desirable level of physical and biological properties.

Other features of the present invention will be pointed out in thefollowing description and claims.

DETAILED DESCRIPTION OF THE PRESENT INVENTION

The present invention provides novel difunctionalized aromatic compoundsand absorbable polymers derived from them. The present invention isdesigned to extend the usefulness of aromatic compounds while retainingtheir inherent biological properties. The aromatic compounds arefunctionalized with safe and biocompatible molecules (e.g., glycolicacid, lactic acid, caprolactone, and dioxanone). The noveldifunctionalized aromatic compounds of the present invention areexpected to have controllable hydrolysis profiles, improvedbioavailability, improved efficacy, and enhanced functionality.

Some of the difunctionalized aromatic compounds of the present inventioncan be monomers from which polymers can be made that are useful formedical applications. For example, an aromatic compound can befunctionalized to form functionalized monomers that can then bepolymerized to form absorbable polymers (e.g., polyesters, polyamides,polyester amides, polyurethanes, and polyanhydrides). It can beadvantageous for the monomers that are to be polymerized to have atleast two active sites (e.g., 2 or 3) for polymerization. These activesites include hydroxyl, amino, and carboxylic acid groups (e.g., twohydroxyl groups, a hydroxyl group and a carboxylic acid, a hydroxylgroup and an amine group, a carboxylic acid group and an amino group,and two carboxylic acid groups). The difunctionalized aromatic compoundswith at least two active sites can also be copolymerized with selecteddifunctional molecules (e.g., dicarboxylic acids, dialcohols,diisocyanates, amino-alcohols, hydroxy-carboxylic acids, and diamines)based on the starting difunctionalized aromatic to form absorbablepolymers. The polymers (and copolymers) of the present invention canalso be further reacted/polymerized to form additional useful polymersof the present invention.

The definitions and examples provided in this application are notintended to be limiting, unless specifically stated.

Ar, as used herein, is an aromatic moiety that typically has 1, 2, 3, 4,5, or 6 aromatic rings (e.g., phenyl) and optionally bear one or moresubstituents (e.g., 1, 2, 3, 4, 5, or 6) on one of the aromatic rings.Additional examples of the number of aromatic groups present in thearomatic include (a) 1, 2, and 3; (b) 1 and 2; and, (c) 1. Aromatics canbe bioactive substances occurring widely in food plants that are eatenregularly by substantial numbers of animals and people and have beenfound to be safe compounds.

The aromatic rings of the Ar group can be fused together (e.g,.naphthyl), bonded together (e.g., bi-phenyl), or linked together via alinking group. Typical linking groups include, O, S(O)₀₋₂, NH (or asubstituted amine, e.g., C₁₋₆ alkyl, phenyl, or benzyl), C₁₋₆ alkylene,or a C₁₋₆ alkylene wherein one or two of the alkylene carbon atoms isreplaced by one or two of the previously noted heteroatoms. The aromaticrings of the Ar group can also be fused to heteroaryl rings and/ornon-aromatic rings. Examples of heteroaryl rings include 5-6 memberedrings consisting of carbon atoms and 0-4 heteroatoms selected from O, N,and S(O)₀₋₂. Examples of non-aromatic rings include 5-6 memberedcarbocyclic or heterocyclic rings consisting of carbon atoms and 0-3heteroatoms selected from O, N, and S(O)₀₋₂. The non-aromatic rings canconsist of 0-2 ring double bonds as well as 0-2 carbonyl groups attachedto the ring. Examples of non-aromatic rings include pyran and pyran-one.The non-aromatic rings can also be substituted by 1-2 carbonyl groups,in addition to other substituents defined elsewhere. When more than onearomatic ring is present (e.g., two phenyl rings), then they can beseparated by a heteroaryl or non-aromatic ring as described above. Forexample, a phenyl ring can be bound to a chromene-2-one.

Examples of Ar include the following:

The Ar group of the present invention is substituted or unsubstituted.When substituted, it can be substituted with (a) 1, 2, 3, 4, 5 or 6 Rgroups; (b) 1, 2, or 3 R groups; (c) 1 or 2 R; or (d) 1 R.

Examples of substituent R include H, ═O, O-glycosides, —(CH₂)₀₋₂—OR^(a),—(CH₂)₀₋₂—C₆H₅, —(CH₂)₀₋₂—CHO, Cl, F, Br, I, —(CH₂)₀₋₂—OC(O)—R^(a),—(CH₂)₀₋₂—CO₂—R^(a), —(C(CH₃))₀₋₂—CO₂—R^(a),—(CH₂)₀₋₂—CO₂—(CH₂)₁₋₂—CO₂—R^(a), —(C(CH₃))₀₋₂—CO₂—(CH₂)₁₋₂—CO₂—R^(a),—(CH₂)₀₋₂—CO—R^(a), —O(CH₂)₀₋₂—C₆H₅, —O(CH₂)₁₋₂—CO ₂—R^(a),—O(C(CH₃))₁₋₂—CO₂—R^(a), —O(CH₂)₁₋₂—CO—R^(a), —CO₂(CH₂)₁₋₂—CO₂—R^(a),—CO₂(C(CH₃))₁₋₂—CO₂—R^(a), —(CH₂)₀₋₂—NO₂, —(CH₂)₀₋₂—NR^(a)R^(a),—(CH₂)₀₋₂—NR^(a)COR^(a), —(CH₂)₀₋₂—NR^(a)C(O)(CH₂)₁₋₂—OR^(a), —C₆H₅,—C₆H₅OR^(a), and —C₆H₅—CH═CHCO₂R^(a).

Examples of R^(a) include H and C₁₋₆ alkyl;

As described herein, the difunctionalized aromatic compounds andpolymers of the present invention are expected to be useful in medicalapplications/medical devices. Medical application/medical devices, asused herein, encompass medical and biomedical applications and includeall types of applications involved in the practice of medicine thatwould benefit from a material that decomposes harmlessly within a knownperiod of time. Examples include medical and surgical devices, whichinclude drug delivery systems (e.g., a site-specific or systemic drugdelivery systems or matrices), tissue engineering (e.g., tissuescaffold), stent coatings, stents, porous devices, implantable medicaldevices, molded articles (e.g., vascular grafts, stents, bone plates,sutures, implantable sensors, and barriers for surgical adhesionprevention), wound closure devices (e.g., surgical clips, staples, andsutures), coatings (e.g., for endoscopic instruments, sutures, stents,and needles), fibers or filaments (which may be attached to surgicalneedles or fabricated into materials including sutures or ligatures,multifilament yarn, sponges, gauze, tubes, and sheets for typing up andsupporting damaged surface abrasions), rods, films (e.g., adhesionprevention barriers), knitted products, foodstuffs, nutritionalsupplements, nutriceuticals, cosmetics, pharmaceuticals, biodegradablechewing gums, flavors, enhanced drugs, drug intermediates, cancerpreventing agents, antioxidants, controlled release preparations, andsolvents for drugs. Examples of knitted products, woven or non-woven,and molded products include: burn dressings; hernia patches; medicateddressings; fascial substitutes; gauze, fabric, sheet, felt, or spongefor liver hemostasis; gauze bandages; arterial graft or substitutes;bandages for skin surfaces; suture knot clip; orthopedic pins, clamps,screws, and plates; clips (e.g., for vena cava); staples; hooks,buttons, and snaps; bone substitutes (e.g., mandible prosthesis);intrauterine devices (e.g., spermicidal devices); draining or testingtubes or capillaries; surgical instruments; vascular implants orsupports; vertebral discs; extracorporeal tubing for kidney andheart-lung machines; and, artificial skin.

As used herein, “polymer” includes both polymers and copolymersdepending on the number of different monomers used.

The present invention provides novel difunctionalized aromatic compoundsof formula I or a pharmaceutically acceptable salt thereof:

[R′—(X)_(a)—OC(O)]_(p)—Ar—[NR′—(Y)_(b)—R′]_(q)  I

wherein:

Ar is an aromatic ring substituted with 1, 2, or 3 R groups;

X is independently at each occurrence selected from:

—CH₂COO— (glycolic acid moiety);

—CH(CH₃)COO— (lactic acid moiety);

—CH₂CH₂OCH₂COO— (dioxanone moiety);

—CH₂CH₂CH₂CH₂CH₂COO— (caprolactone moiety);

—(CH₂)_(y)COO— where y is independently selected from 2, 3, 4, 6, 7, 8,9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, and 24; and,

—(CH₂CH₂O)_(z)CH₂COO— where z is independently selected from 2, 3, 4, 5,6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, and24;

Y is independently at each occurrence selected from:

—COCH₂O— (glycolic ester moiety);

—COCH(CH₃)O— (lactic ester moiety);

—COCH₂OCH₂CH₂O— (dioxanone ester moiety);

—COCH₂CH₂CH₂CH₂CH₂O— (caprolactone ester moiety);

—CO(CH₂)_(m)O— where m is selected from 2, 3, 4, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, and 24; and,

—COCH₂O(CH₂CH₂O)_(n) — where n is selected from 2, 3, 4, 5, 6, 7, 8, 9,10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, and 24;

R′ is selected from hydrogen, benzyl, and C₁₋₆ alkyl;

p and q are independently selected from 0, 1, 2, 3, and 4, provided thatp+q total 2, 3, or 4;

a and b, are independently selected from 0, 1, 2, 3, and 4, providedthat a+b total from 1, 2, 3, 4, 5, or 6;

R is independently selected from —O—(X)_(c)—R′ and —O—(Y)_(c)—R′;

c is independently selected from 0, 1, 2, 3, and 4;

alternatively, R is independently selected from H, ═O, O-glycosides,—(CH₂)₀₋₂—OR^(a), —(CH₂)₀₋₂—C₆H₅, —(CH₂)₀₋₂—CHO, Cl, F, Br, I,—(CH₂)₀₋₂—OC(O)—R^(a), —(CH₂)₀₋₂—CO₂—R^(a), —(C(CH₃))₀₋₂; —CO₂—R^(a),—(CH₂)₁₋₂—CO₂—(CH₂)₁₋₂—CO₂—R^(a), —(C(CH₃))₁₋₂—CO₂—(CH₂)₁₋₂—CO₂—R^(a),—(CH₂)₀₋₂—CO—R^(a), —O(CH₂)₀₋₂—C₆H₅, —O(CH₂)₁₋₂—CO₂—R^(a),—O(C(CH₃))₁₋₂—CO₂—R^(a), —O(CH₂)₁₋₂—CO—R^(a), —(CH₂)₀₋₂—NO₂,—(CH₂)₀₋₂—NR^(a)R^(a), —(CH₂)₀₋₂—NR^(a)COR^(a), —(CH₂)₁₋₂—NR^(a)C(O)(CH₂)₁₋₂—OR^(a), —C₆H₅, —C₆H₅OR^(a), and —C₆H₅—CH═CHCO₂R^(a);and,

R^(a) is independently selected from H and C₁₋₆ alkyl.

Additional examples of p and q include (a) 0, 1, 2, and 3, provided thatp+q total 1, 2, or 3; and (b) 0, 1, and 2, provided that p+q total 1, 2,or 3.

Additional examples of a and b include (a) 0, 1, 2, and 3, provided thata+b total from 1, 2, 3, or 4; and (b) 0, 1, and 2, provided that a+btotal from 1, 2, or 3.

Additional examples of c include (a) 0, 1, 2, and 3; and (b) 0, 1, and2.

The group represented by X is attached via its carbon terminus to theoxygen group of the carboxyl. The group represented by Y is attached viaits carbonyl terminus to the oxygen or nitrogen group of the aminogroup.

The rate of hydrolysis of the difunctionalized aromatic compounds willdepend upon a number of factors, including the functionalization speciesused and the number of functionalization species present on thedifunctionalized aromatic (e.g., 1-6). Glycolic acid modified aromaticsshould hydrolyze faster than dioxanone modifies ones, where as lacticacid and caprolactone modified aromatics should take much longer tohydrolyze than glycolic acid and dioxanone modified aromatics.Furthermore, it is expected that the rate of hydrolysis will increasewith the increase in the value of p and q. Thus, the desired time rangemay be obtained by altering the number and type of functionalizationspecies used to functionalize the aromatics.

The present invention also provides novel difunctionalized aromaticcompounds of formula I, wherein:

y is independently selected from 2, 3, and 4;

z is independently selected from 2, 3, and 4;

p is independently selected from 1, 2, and 3; and,

q is selected from 1, 2, and 3.

The present invention also provides novel difunctionalized aromaticcompounds of formula I, wherein:

X is independently at each occurrence selected from:

—CH₂COO—;

—CH(CH₃)COO—;

—CH₂CH₂OCH₂COO—; and,

—CH₂CH₂CH₂CH₂CH₂COO—; and,

Y is independently at each occurrence selected from:

—COCH₂O—;

—COCH(CH₃)O—;

—COCH₂OCH₂ CH₂O—;

—COCH₂CH₂CH₂CH₂CH₂O—;

p and q are independently selected from 0, 1, 2, and 3, provided thatp+q total 2 or 3;

a and b, are independently selected from 0, 1, 2, and 3, provided thata+b total from 1, 2, 3, or 4; and,

c is independently selected from 0, 1, 2, and 3.

The present invention also provides novel difunctionalized aromaticcompounds of formula I, wherein: X is selected from:

X is independently at each occurrence selected from: —CH₂COO— and—CH(CH₃)COO—;

Y is independently at each occurrence selected from: —COCH₂O— and—COCH(CH₃)O—;

a and b, are independently selected from 0, 1, and 2, provided that a+btotal from 1, 2, 3, or 4; and,

c is independently selected from 0, 1, and 2.

The present invention also provides novel difunctionalized aromaticcompounds of formula Ia-Ic:

The present invention also provides novel difunctionalized aromaticcompounds of formula IIa-IIc:

The present invention also provides novel difunctionalized aromaticcompounds of IIIa-IIIc:

The present invention also provides a blend comprising one or more ofthe functionalization species with one or more species of aromaticcompounds.

The present invention also provides polymers formed from thedifunctionalized aromatic compounds of this invention that aredifunctional, that is those species having more than one hydroxyl,carboxyl, ester, amino, cyano, or other polymerizable group. If thedifunctionalized aromatic of the present invention only has onepolymerizable moiety, then it can only be used as an endcap. Polymers ofthe difunctionalized aromatic compounds are expected to have specificranges over which they release the active aromatic moiety. One can blendpolymers made from difunctionalized aromatic compounds derived from oneor more of the functionalization species and one or more species ofaromatic moieties to obtain the release range desired for the specificapplication into the body of a mammalian, including a human or theenvironment. This release range varies with the species used forfunctionalization as well as the aromatic compound. The combinations orblends of these entities may comprise an amount of from 0.5% to 99.5% byweight of each species.

In addition, the monomers of the present invention may be polymerized toform absorbable polymers that display excellent physical, chemical, andbiological properties, which make them useful in medical applications.The polymers of the present invention are expected to form non-toxicdegradation products by hydrolytic chain cleavage under physiologicalconditions. The novel polymers of the present invention are expected tohave increased rate of degradation and bioresorption as well ascontrollable degradation profile in comparison to the currentlyavailable polymers.

For example, a phenol, such as resorcinol, can be functionalized to forma reactive compound, which can be polymerized to form an absorbablepolymer with a specific absorption profile. Similarly, each thearomatics described above can be functionalized to form reactivemonomers. The polymers derived from these monomers will have uniquephysical and biological properties with absorption profiles that arecontrollable.

Thus, the present invention provides novel polymers formed fromdifunctionalized aromatic compounds of formula I.

The difunctionalized aromatic compounds of the present invention can bepolymerized via conventional polymerization process using diol, triols,dicarboxylic acids, tricarboxylic acids, diamines, or triamines based onthe starting difunctionalized or trifunctionalized aromatics, includingthose processes that synthesize polymers traditionally consideredhydrolytically stable and non-biodegradable.

The present invention encompasses a variety of different polymers, someof which are copolymers. The polymers of the present invention include(a) polymers formed from one functionalized aromatic; (b) copolymersformed from more than one (e.g., 2, 3, or 4) type of difunctionalizedaromatic (e.g., a blend of difunctionalized aromatic compounds that ispolymerized); (c) copolymers formed from at least one type ofdifunctionalized aromatic having at least two active sites (e.g., 2 or3) and a difunctional molecule (e.g., dicarboxylic acids, dialcohols,diisocyanates, amino-alcohols, hydroxy-carboxylic acids, and diamines);and (d) copolymers formed from at least one of the polymers of (a)-(c)and at least one lactone monomer (e.g., glycolide, lactide,ε-caprolactone, trimethylene carbonate, and p-dioxanone). The absorptionprofile of the polymers of the present invention will depend upon anumber of factors, including the functionalization species used and thenumber of functionalization species present on the difunctionalizedaromatic (e.g., 1-6). Glycolic acid based polymers should hydrolyzefaster than dioxanone based, where as lactic acid and caprolactone basedpolymers should take much longer to hydrolyze than glycolic acid anddioxanone based polymers. The desired time range may be obtained byaltering the number and type of functionalization species as well as thenumber of different difunctionalized aromatic compounds (e.g., a blendof two or more functionalized aromatics). The desired time range willalso be impacted by moieties used for co-polymerization (e.g.,difunctional compounds or lactone monomers).

The difunctionalized aromatic polymers can be used in various medicalapplications described herein or can be further polymerized with lactonemonomers, such as glycolide, lactide, ε-caprolactone, trimethylenecarbonate, and p-dioxanone, and the resulting absorbable functionalizedaromatic/lactone copolymers can be used in the various medicalapplications described herein.

As noted above, more than one of the difunctionalized aromatic compoundsof the present invention can be blended and polymerized to form adifunctionalized aromatic copolymer. The difunctionalized aromaticcopolymers can be used in various medical applications described hereinor can be further polymerized with lactone monomers, such as glycolide,lactide, ε-caprolactone, trimethylene carbonate, and p-dioxanone, andthe resulting absorbable polymers can also have the medical applicationsdescribed herein.

As noted above, the difunctionalized aromatic compounds of the presentinvention with at least two reactive sites can be polymerized withdifunctional molecules (e.g., dicarboxylic acids, dialcohols,diisocyanates, amino-alcohols, hydroxy-carboxylic acids, and diamines)to form absorbable polymers, including but not limited to polyesters,polyester amides, polyurethanes, polyamides, and polyanhydrides bysimple polycondensation reactions. The functionalizedaromatic/difunctional molecule polymers can be used in various medicalapplications or can be further polymerized with lactone monomers, suchas glycolide, lactide, ε-caprolactone, trimethylene carbonate, andp-dioxanone, and the resulting absorbable polymers potential have themedical applications described above.

In another example of the present invention, functionalized dihydroxyaromatic compounds of the present invention can be used in thepreparation of polyester amides by reacting with dicarboxylic acidcompounds. Dicarboxylic acids useful in the present invention have thefollowing structure:

HOOC—R—COOH

wherein R is selected from saturated and unsaturated, substituted andunsubstituted alkyl, aryl and alkylaryl groups having from 1, 2, 3, 4,5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, and 18 carbon atoms

In another example of the present invention, functionalized dicarboxylicacid aromatic compounds of the present invention can be used in thepreparation of polyesters by reacting with the dialcohol (i.e., diol)compounds. Dialcohols useful in the present invention have the followingstructure:

HO—R—OH

wherein R is selected from saturated and unsaturated, substituted andunsubstituted alkyl, aryl and alkylaryl groups having from 2, 3, 4, 5,6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, and 18 carbon atoms.Alternatively, polyalkylene oxides have weight average molecular weightsfrom about 500-5,000 can be used as a diol (i.e., a polydiol). Suitablediols or polydiols for use in the present invention are diol or diolrepeating units with up to 8 carbon atoms. Examples of suitable diolsinclude 1,2-ethanediol (ethylene glycol); 1,2-propanediol (propyleneglycol); 1,3-propanediol; 1,4-butanediol; 1,5-pentanediol;1,3-cyclopentanediol; 1,6-hexanediol; 1,4-cyclohexanediol;1,8-octanediol; and, combinations thereof. Examples of polydiols includepolyethylene glycol and polypropylene glycol with weight averagemolecular weights of 500-5000.

In another example of the present invention, functionalized dihydroxyaromatic compounds of the present invention can be used in thepreparation of polyurethanes by reacting with diisocyante compounds.Examples of diisocyanates include hexamethylene diisocyante, lysinediisocyanate, methylene diphenyl diisocyanate (e.g., MDI), hydrogenatedMDI (e.g., methylene dicyclohexyl diisocyanate), and isophoronediisocyanate. .

In another example of the present invention, functionalizedhydroxy-amino aromatic compounds of the present invention can be used inthe preparation of polyesteramides by reacting with dicarboxylic acidcompounds described above.

In another example of the present invention, functionalized dicarboxylicacid aromatic compounds of the present invention can be used in thepreparation of polyesteramides by reacting with the amino-alcoholcompounds. Amino-alcohols useful in the present invention have thefollowing structure:

HO—R—NH₂

wherein R is selected from saturated and unsaturated, substituted andunsubstituted alkyl, aryl and alkylaryl groups having from 2, 3, 4, 5,6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, and 18 carbon atoms.

In another example of the present invention, functionalizedhydroxy-carboxylic acid aromatic compounds of the present invention canbe used in the preparation of polyesters by reacting withhydroxycarboxylic acid compounds. Hydroxycarboxylic acids useful in thepresent invention have the following structure:

HO—R—COOH

wherein R is selected from saturated and unsaturated, substituted andunsubstituted alkyl, aryl and alkylaryl groups having from 1, 2, 3, 4,5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, and 18 carbon atoms,

In another example of the present invention, functionalizedamino-carboxylic acid aromatic compounds of the present invention can beused in the preparation of polyesteramides by reacting with thehydroxycarboxylic acid compounds described above.

In another example of the present invention, functionalized dicarboxylicacid aromatic compounds of the present invention can be used in thepreparation of polyamides by reacting with the diamine compounds.Diamines useful in the present invention have the following structure:

H₂N—R—NH₂

wherein R is selected from saturated and unsaturated, substituted andunsubstituted alkyl, aryl and alkylaryl groups having from 2, 3, 4, 5,6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, and 18 carbon atoms.Alternatively, polyalkylene oxides that are diamines with weight averagemolecular weights from about 500-5,000 can be used.

In another example of the present invention, functionalized dicarboxylicacid aromatic compounds of the present invention can be used in thepreparation of polyanhydrides by reacting with the dicarboxylic acidcompounds described above.

The difunctionalized aromatic compounds of the present invention havingmore than two reactive groups (e.g., 3) are expected to be useful in thepreparation of cross linked hydrogels and are prepared

Examples of polymers of the present invention have weight-averagemolecular weights above about 20,000 daltons or above about 100,000daltons, calculated from gel permeation chromatography (GPC) relative topolystyrene standards in tetrahydrofuran (THF) without furthercorrection.

The polymers of the present invention should be able to be processed byknown methods commonly employed in the field of synthetic polymers toprovide a variety of useful articles with valuable physical and chemicalproperties. The useful articles can be shaped by conventionalpolymer-forming techniques such as extrusion, compression molding,injection molding, solvent casting, and wet spinning Shaped articlesprepared from the polymers are expected to be useful as degradabledevices for medical implant applications.

The present invention also relates to a composition, comprising: atleast two (e.g., 2, 3, 4, or 5) functional aromatic compounds of thepresent invention.

The present invention also relates to a composition, comprising: atleast one functionalized aromatic, wherein the composition is suitablefor use as at least one of the following: (a) a solvent for drugs; (b) anutritional compound; (c) a cosmetic: and, (d) a pharmaceutical. Each ofthe compositions may further comprise an additional component suitablefor such composition. For example, when the composition is suitable foruse as a cosmetic it may further comprise: one or more cosmeticingredients. Also, when the composition is suitable for use as apharmaceutical it may further comprise: one or more pharmaceuticallyacceptable excipients. In addition, each of the compositions maycomprise a difunctionalized aromatic derived from a aromatic having aproperty useful to that type of composition. For example, the startingaromatic may be (a) a nutritional supplement or a food intermediary; (b)an anticancer agent; (c) an antimicrobial agent; (d) ananti-inflammatory agent; (e) a pain-reducer; and, (f) an antioxidantagent. Also, the compositions may further comprise one of agents(a)-(f).

The compositions of the present invention may be suitable foradministration via a route selected from oral, enteral, parenteral,topical, transdermal, ocular, vitreal, rectal, nasal, pulmonary, andvaginal.

The implantable medical devices of the present invention, comprise: atleast one absorbable polymer of the present invention. For example, apolymer of the present invention can be combined with a quantity of abiologically or pharmaceutically active compound sufficient to betherapeutically effective as a site-specific or systemic drug deliverysystem (see Gutowska et al., J. Biomater. Res., 29, 811-21 (1995) andHoffman, J. Controlled Release, 6, 297-305 (1987)). Another example ofthe present invention is a method for site-specific or systemic drugdelivery by implanting in the body of a patient in need thereof animplantable drug delivery device comprising a therapeutically effectiveamount of a biologically or a physiologically active compound incombination with at least one absorbable polymer of the presentinvention.

In another example, at least one polymer of the present invention isformed into a porous device (see Mikos et al., Biomaterials, 14, 323-329(1993) or Schugens et al., J. Biomed. Mater. Res., 30, 449-462 (1996))to allow for the attachment and growth of cells (see Bulletin of theMaterial Research Society, Special Issue on Tissue Engineering (GuestEditor: Joachim Kohn), 21(11), 22-26 (1996)). Thus, the presentinvention provides a tissue scaffold comprising a porous structure forthe attachment and proliferation of cells either in vitro or in vivoformed from at least one absorbable polymer of the present invention

The present invention also relates to an article (e.g., an implantablemedical device), comprising: a metal or polymeric substrate havingthereon a coating, wherein the coating, comprises: at least one polymerof the present invention.

The present invention also relates to a molded article prepared from atleast one polymer of the present invention.

The present invention also relates to a controlled drug delivery system,comprising: at least one polymer of the present invention physicallyadmixed with a biologically or pharmacologically active agent. Forexample, the controlled drug delivery system can comprise: abiologically or pharmacologically active agent coated with at least onepolymer of the present invention.

The present invention also relates to a controlled drug delivery system,comprising: a biologically or pharmacologically active agent physicallyembedded or dispersed into a polymeric matrix formed from at least onepolymer of the present invention.

The present invention also relates to a tissue scaffold having a porousstructure for the attachment and proliferation of cells, either in vitroor in vivo, formed from one least one polymer of the present invention.

The present invention also relates to a composition, comprising: atleast one polymer of the present invention, which has been furtherpolymerized with at least one lactone monomer selected from: glycolide,lactide, p-dioxanone, trimethylene carbonate, and caprolactone.

The present invention also relates to an implantable biomedical device,comprising: at least one polymer that has been further polymerized withat least one lactone monomer.

The present invention also relates to a biodegradable chewing gumcomposition, comprising: an effective amount of at least one polymerthat has been further polymerized with at least on lactone monomer.

The present invention also relates to an article (e.g., an implantablemedical device), comprising: a metal or polymeric substrate and havingthereon a coating, wherein said coating comprises at least one polymerthat has been further polymerized with at least one lactone monomer.

The present invention also relates to a molded article prepared from atleast one polymer that has been further polymerized with at least onelactone monomer.

The present invention also relates to a monofilament or multifilamentprepared from at least one polymer that has been further polymerizedwith at least one lactone monomer.

The present invention also relates to a controlled drug delivery system,comprising: at least one polymer that has been further polymerized withat least one lactone monomer, which has been physically admixed with abiologically or pharmacologically active agent.

The present invention also relates to a controlled drug delivery system,comprising: a biologically or pharmacologically active agent physicallyembedded or dispersed into a polymeric matrix formed from at least onepolymer that has been further polymerized with at least one lactonemonomer.

The present invention also relates to a tissue scaffold having a porousstructure for the attachment and proliferation of cells, either in vitroor in vivo, formed from at least one polymer that has been furtherpolymerized with at least one lactone monomer.

The present invention also relates to low molecular weight polymers oroligomers of the difunctionalized aromatic compounds of the presentinvention that are further reacted to form reactive end groups (e.g.,isocyanates, expoxides, and acrylates). Low-molecular weight polymers oroligomers as used herein means a polymer having a number averagemolecular weight of about 500-20,000 or 500-10,000. For example, some ofthe difunctionalized aromatic compounds behave chemically like diols.They can be reacted with dicarboxylic acids to form polyesters, whichare usually hydroxyterminated. These hydroxyterminated oligomers can befurther reacted to form isocyanates, epoxides and acrylates. Similarlythe difunctionalized aromatic compounds can be reacted with isocyanatesto make urethanes. Thus, the present invention also includes acomposition, comprising: at least one polymer of the present invention,which has been further reacted to form reactive end groups.

The present invention also relates to polymers made fromdifunctionalized aromatic compounds that have been sterilized bycobalt-60 radiation, electron beam radiation, and/or ethylene oxide.

“Bioabsorbable” or “absorbable” as used herein means that the materialreadily reacts or enzymatically degrades upon exposure to bodily tissuefor a relatively short period of time, thereby experiencing asignificant weight loss in that short period of time. Completebioabsorption/absorption should take place within twelve months,although it may be complete within nine months or within six months. Inthis manner, the polymers of the present invention can be fabricatedinto medical and surgical devices, which are useful for a vast array ofapplications requiring complete absorption within a relatively shorttime period.

The biological properties of the bioabsorbable polymers of the presentinvention used to form a device or part thereof, as measured by itsabsorption rate and its breaking strength retention in vivo (BSR), canbe varied to suit the needs of the particular application for which thefabricated medical device or component is intended. This can beconveniently accomplished by varying the ratio of components of thepolymer chosen.

“Pharmaceutically acceptable salts” refer to derivatives of thedisclosed compounds wherein the parent compound is modified by makingacid or base salts thereof. Examples of pharmaceutically acceptablesalts include, but are not limited to, mineral or organic acid salts ofbasic residues such as amines; alkali or organic salts of acidicresidues such as carboxylic acids; and the like. The pharmaceuticallyacceptable salts include the conventional non-toxic salts or thequaternary ammonium salts of the parent compound formed, for example,from non-toxic inorganic or organic acids. For example, suchconventional non-toxic salts include, but are not limited to, thosederived from inorganic and organic acids selected from 1,2-ethanedisulfonic, 2-acetoxybenzoic, 2-hydroxyethanesulfonic, acetic,ascorbic, benzenesulfonic, benzoic, bicarbonic, carbonic, citric,edetic, ethane disulfonic, ethane sulfonic, fumaric, glucoheptonic,gluconic, glutamic, glycolic, glycollyarsanilic, hexylresorcinic,hydrabamic, hydrobromic, hydrochloric, hydroiodide, hydroxymaleic,hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl sulfonic,maleic, malic, mandelic, methanesulfonic, napsylic, nitric, oxalic,pamoic, pantothenic, phenylacetic, phosphoric, polygalacturonic,propionic, salicyclic, stearic, subacetic, succinic, sulfamic,sulfanilic, sulfuric, tannic, tartaric, and toluenesulfonic.

The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound that contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, non-aqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Lists of suitable salts are found in Remington'sPharmaceutical Sciences, 18th ed., Mack Publishing Company, Easton, Pa.,1990, p 1445, the disclosure of which is hereby incorporated byreference.

“Therapeutically effective amount” includes an amount of a compound ofthe present invention that is effective when administered alone or incombination to treat the desired indication.

“Alkyl” includes both branched and straight-chain saturated aliphatichydrocarbon groups having the specified number of carbon atoms. C₁₋₆alkyl, for example, includes C₁, C₂, C₃, C₄, C₅, and C₆ alkyl groups.Examples of alkyl include methyl, ethyl, n-propyl, i-propyl, n-butyl,s-butyl, t-butyl, n-pentyl, s-pentyl, and n-hexyl.

Polymers of the present invention may be made in the form of randomcopolymers or block copolymers. A coupling agent may also be added tothe polymers of the present invention. A coupling agent is a reagentthat has a least two functional groups that are capable of covalentlybonding to two different monomers. Examples of coupling agents includetrifunctional or tetrafunctional polyols, oxycarboxylic acids, andpolybasic carboxylic acids (or acid anhydrides thereof). Other couplingagents include the difunctional groups (e.g., diols, diacids, diamines,and hydroxy-acids) previously discussed. The addition of the couplingagents causes the branching of long chains, which can impart desirableproperties in the molten state to the pre-polymer. Examples ofpolyfunctional coupling agents include trimethylol propane, glycerin,pentaerythritol, malic acid, citric acid, tartaric acid, trimesic acid,propane tricarboxylic acid, cyclopentane tetracarboxylic anhydride, andcombinations thereof.

A “pre-polymer” is a low-molecular weight polymer, as previouslydefined, that have reactive endgroups (e.g., hydroxy groups) that can befurther reactive with, for example, the lactone monomers.

The amount of coupling agent to be added before gelation occurs is afunction of the type of coupling agent used and the polymerizationconditions of the polymer or molecular weight of the pre-polymer towhich it is added. Generally in the range of from about 0.1 to about 10mole percent of a trifunctional or a tetrafunctional coupling agent maybe added based on the moles of polymers present or anticipated from thesynthesis.

The polymerization of a polyester of the present invention can beperformed under melt polycondensation conditions in the presence of anorganometallic catalyst at elevated temperatures. The organometalliccatalyst can be a tin-based catalyst (e.g., stannous octoate or dibutyltin oxide). The catalyst can be present in the mixture at a mole ratioof diol, dicarboxylic acid, and optionally lactone monomer to catalystwill be in the range of from about 15,000/1 to 80,000/1. The reactioncan be performed at a temperature not less than about 120° C. underreduced pressure. Higher polymerization temperatures may lead to furtherincreases in the molecular weight of the copolymer, which may bedesirable for numerous applications. The exact reaction conditionschosen will depend on numerous factors, including the properties of thepolymer desired, the viscosity of the reaction mixture, and the glasstransition temperature and softening temperature of the polymer. Desiredreaction conditions of temperature, time and pressure can be readilydetermined by assessing these and other factors. Generally, the reactionmixture will be maintained at about 220° C. The polymerization reactioncan be allowed to proceed at this temperature until the desiredmolecular weight and percent conversion is achieved for the copolymer,which will typically take about 15 minutes to 24 hours. Increasing thereaction temperature generally decreases the reaction time needed toachieve a particular molecular weight.

Polymerization conditions for the preparation of other types of polymersof the present invention (e.g., polyamides) are described in theliterature. Those skilled in the art will recognize that the polymersdescribed herein can be made from known procedures.

Copolymers of the absorbable polymers of the present invention can beprepared by preparing a pre-polymer under melt polycondensationconditions, then adding at least one lactone monomer or lactonepre-polymer. The mixture could then be subjected to the desiredconditions of temperature and time to copolymerize the pre-polymer withthe lactone monomers.

A lactone pre-polymer is a pre-polymer formed by ring openingpolymerization with a known initiator (e.g., ethylene glycol, diethyleneglycol, glycerol, or other diols or triols).

The molecular weight of the pre-polymer as well as its composition canbe varied depending on the desired characteristic, which the pre-polymeris to impart to the copolymer. For example, the pre-polymers of thepresent invention, from which the copolymer is prepared, generally havea molecular weight that provides an inherent viscosity between about 0.2to about 2.0 deciliters per gram (dl/g) as measured in a 0.1 g/dlsolution of hexafluoroisopropanol at 25° C. Those skilled in the artwill recognize that the pre-polymers described herein can also be madefrom mixtures of more than one diol or dicarboxylic acid.

One of the beneficial properties of the polyesters of the presentinvention is that the ester linkages are hydrolytically unstable, andtherefore the polymer is bioabsorbable because it readily breaks downinto small segments when exposed to moist bodily tissue. In this regard,while it is envisioned that co-reactants could be incorporated into thereaction mixture of the dicarboxylic acid and the diol for the formationof the polyester pre-polymer, it is preferable that the reaction mixturedoes not contain a concentration of any co-reactant which would renderthe subsequently prepared polymer nonabsorbable. The reaction mixturecan be substantially free of any such co-reactants if the presencethereof results in a nonabsorbable polymer.

The polymers of the present invention can be melt processed by numerousmethods to prepare a vast array of useful devices. These polymers can beinjection or compression molded to make implantable medical and surgicaldevices, especially wound closure devices.

Alternatively, the polymers can be extruded to prepare fibers. Thefilaments thus produced may be fabricated into sutures or ligatures,attached to surgical needles, packaged, and sterilized by knowntechniques. The polymers of the present invention may be spun asmultifilament yarn and woven or knitted to form sponges or gauze, (ornon-woven sheets may be prepared) or used in conjunction with othermolded compressive structures as prosthetic devices within the body of ahuman or animal where it is desirable that the structure have hightensile strength and desirable levels of compliance and/or ductility.Examples include tubes, including branched tubes, for artery, vein, orintestinal repair, nerve splicing, tendon splicing, sheets for typing upand supporting damaged surface abrasions, particularly major abrasions,or areas where the skin and underlying tissues are damaged or surgicallyremoved.

Additionally, the polymers can be molded to form films which, whensterilized, are useful as adhesion prevention barriers. Anotheralternative processing technique for the polymers of the presentinvention includes solvent casting, particularly for those applicationswhere a drug delivery matrix is desired.

The polymers of the present invention can be used to coat a surface of asurgical article to enhance the lubricity of the coated surface. Thepolymer may be applied as a coating using conventional techniques. Forexample, the polymer may be solubilized in a dilute solution of avolatile organic solvent (e.g. acetone, methanol, ethyl acetate, ortoluene), and then the article can be immersed in the solution to coatits surface. Once the surface is coated, the surgical article can beremoved from the solution where it can be dried at an elevatedtemperature until the solvent and any residual reactants are removed.

For coating applications, the polymer should exhibit an inherentviscosity, as measured in a 0.1 gram per deciliter (g/dl) ofhexafluoroisopropanol (HFIP), between about 0.05-2.0 dl/g or about0.10-0.80 dl/g. If the inherent viscosity were less than about 0.05dl/g, then the polymer may not have the integrity necessary for thepreparation of films or coatings for the surfaces of various surgicaland medical articles. On the other hand, it is possible to use polymerswith an inherent viscosity greater than about 2.0 dl/g, though it may bedifficult to do so.

Although numerous surgical articles (including but not limited toendoscopic instruments) can be coated with the polymer of the presentinvention to improve the surface properties of the article, specificsurgical articles include surgical sutures, stents, and needles. Forexample the surgical article can be a suture, which can be attached to aneedle. The suture can be a synthetic absorbable suture. These suturesare derived, for example, from homopolymers and copolymers of lactonemonomers such as glycolide, lactide, ε-caprolactone, 1,4-dioxanone, andtrimethylene carbonate. The suture can be a braided multifilament suturecomposed of polyglycolide or poly(glycolide-co-lactide).

The amount of coating polymer to be applied on the surface of a braidedsuture can be readily determined empirically, and will depend on theparticular copolymer and suture chosen. Ideally, the amount of coatingcopolymer applied to the surface of the suture may range from about0.5-30 percent of the weight of the coated suture or from about 1.0-20weight percent, or from 1-5 percent by weight. If the amount of coatingon the suture were greater than about 30 weight percent, then it mayincrease the risk that the coating may flake off when the suture ispassed through tissue

Sutures coated with the polymers of the present invention are desirablebecause they have a more slippery feel, thus making it easier for thesurgeon to slide a knot down the suture to the site of surgical trauma.In addition, the suture is more pliable, and therefore is easier for thesurgeon to manipulate during use. These advantages are exhibited incomparison to sutures which do not have their surfaces coated with thepolymer of the present invention.

When the article of the present invention is a metal stent, the amountof coating applied to the surface of the article is an amount whichcreates a layer with a thickness ranging, for example, between about 2-20 microns on the stent or about 4-8 microns. If the amount of coatingon the stent were such that the thickness of the coating layer wasgreater than about 20 microns, or if the thickness was less than about 2microns, then the desired performance of the stent as it is passedthrough tissue may not be achieved.

When the article of the present invention is a surgical needle, theamount of coating applied to the surface of the article is an amountwhich creates a layer with a thickness ranging, for example, betweenabout 2 -20 microns on the needle or about 4-8 microns. If the amount ofcoating on the needle were such that the thickness of the coating layerwas greater than about 20 microns, or if the thickness was less thanabout 2 microns, then the desired performance of the needle as it ispassed through tissue may not be achieved.

The polymers of the present invention can also be used as apharmaceutical carrier in a drug delivery matrix. To form this matrixthe polymer can be mixed with a therapeutic agent to form the matrix.There are a variety of different therapeutic agents, which can be usedin conjunction with the polymers of the invention. In general,therapeutic agents which may be administered via the pharmaceuticalcompositions of the invention include, antiinfectives such asantibiotics and antiviral agents; analgesics and analgesic combinations;anorexics; antihelmintics; antiarthritics; antiasthmatic agents;anticonvulsants; antidepressants; antidiuretic agents; antidiarrheals;antihistamines; antiinflammatory agents; antimigraine preparations;antinauseants; antineoplastics; antiparkinsonism drugs; antipruritics;antipsychotics; antipyretics, antispasmodics; anticholinergics;sympathomimetics; xanthine derivatives; cardiovascular preparationsincluding calcium channel blockers and beta-blockers such as pindololand antiarrhythmics; antihypertensives; diuretics; vasodilatorsincluding general coronary, peripheral and cerebral; central nervoussystem stimulants; cough and cold preparations, including decongestants;hormones such as estradiol and other steroids, includingcorticosteroids; hypnotics; immunosuppressives; muscle relaxants;parasympatholytics; psychostimulants; sedatives; and tranquilizers; andnaturally derived or genetically engineered proteins, polysaccharides,glycoproteins, or lipoproteins.

The drug delivery matrix may be administered in any suitable dosage formincluding orally, parenterally, subcutaneously as an implant, vaginally,or as a suppository. Matrix formulations containing the polymers of thepresent invention may be formulated by mixing one or more therapeuticagents with the polymer. The therapeutic agent, may be present as aliquid, a finely divided solid, or any other appropriate physical form.Typically, but optionally, the matrix will include one or moreadditives, e.g., nontoxic auxiliary substances such as diluents,carriers, excipients, or stabilizers. Other suitable additives may beformulated with the polymers of the present invention andpharmaceutically active agent. If water is to be used, then it can beuseful to add it just before administration.

The amount of therapeutic agent will be dependent upon the particulardrug employed and medical condition being treated. Typically, the amountof drug represents about 0.001%-70%, 0.001%-50%, or 0.001%-20% by weightof the matrix.

The quantity and type of polymer incorporated into a composition (e.g.,parenterally delivered composition) will vary depending on the releaseprofile desired and the amount of drug employed. The product may containblends of polymers of the present invention to provide the desiredrelease profile or consistency to a given formulation.

The polymers of the present invention, upon contact with body fluidsincluding blood or the like, undergoes gradual degradation (mainlythrough hydrolysis) with concomitant release of the dispersed drug for asustained or extended period (as compared to the release from anisotonic saline solution). This can result in prolonged delivery (e.g.,over 1-2,000 hours or 2-800 hours) of effective amounts (e.g., 0.0001mg/kg/hour to 10 mg/kg/hour) of the drug. This dosage form can beadministered as is necessary depending on the subject being treated, theseverity of the affliction, and the judgment of the prescribingphysician.

Individual formulations of drugs and polymers of the present inventionmay be tested in appropriate in vitro and in vivo models to achieve thedesired drug release profiles. For example, a drug could be formulatedwith a polymer of the present invention and orally administered to ananimal. The drug release profile could then be monitored by appropriatemeans such as, by taking blood samples at specific times and assayingthe samples for drug concentration. Following this or similarprocedures, those skilled in the art will be able to formulate a varietyof formulations.

The new difunctionalized aromatic compounds can have controllablehydrolysis profiles, improved bioavailability, improved efficacy andenhanced functionality. The difunctional compounds can readilypolymerize into biodegradable polyesters, polyester amides,polyurethanes, polyamides, and polyanhydrides, for example, useful formany applications, including biomedical applications, foodstuffs,nutritional supplements, cosmetics, medicaments, coatings and othersreadily apparent to one skilled in the art.

An object of this invention is to combine these molecules, such asglycolic acid, lactic acid, p-dioxanone, ε-caprolactone, —(CH₂)_(y)COO—,where y is one of the integers 2,3,4 and between 6 and 24 inclusive, and—(CH₂CH₂O)_(z) CH₂COO—, where z is an integer between 2 and 24inclusive, with aromatic compound, to form a new chemical entity.Preferential examples of functionalization molecules are glycolic acid,lactic acid, p-dioxanone, and ε-caprolactone. This functionalizationenhances the native value of the aromatic compound by releasing thearomatic moiety by hydrolysis or degradation of the compound. Thecompound degrades under controllable conditions in the environment, inthe body of an animal, for example a mammalian, including a human.

The glycolic acid moiety, lactic acid moiety, dioxanone moiety,caprolactone moiety, moieties of —(CH₂)_(y)COO— where y is one of thenumbers 2,3,4 and 6-24, and moieties of —(CH₂CH₂O)_(z) CH₂COO— where zis an integer between 2 and 24, including 2 and 24, have differenthydrolysis or degradation rates and times over which they release theactive aromatic moiety and thus do the difunctionalized aromatic acidmade from them. The species used for functionalization supplies therelease time or range dictated by the application. Glycolic acid basedcompounds hydrolyze faster than p-dioxanone based, where as lactic acidand caprolactone based compounds take much longer to hydrolyze thanglycolic acid and p-dioxanone based compounds. This desired time rangemay be obtained by using a combination of difunctionalized aromaticcompounds, that is, a blend of two or more functionalized compounds madefrom any two or more of the species glycolide, lactide, dioxanone andpolydioxanone combined with one aromatic compound.

The array of difunctionalized aromatic compounds developed as an aspectof the invention, have a wide range of hydrolysis rates that arecontrollable. The specific moiety or combination of moieties used forfunctionalization yields a compound or mixture with specific hydrolysisranges.

The new difunctionalized aromatic compounds are expected to have morecontrollable hydrolysis profiles, improved bioavailability, improvedefficacy and enhanced functionality. The difunctional compoundspolymerize into biodegradable polymers, for example, useful forapplications, including biomedical applications, foodstuffs, cosmetics,medicaments, coatings and other uses readily apparent to one skilled inthe art.

FUNCTIONALIZATION

The functionalized aromatic compounds of the present invention aretypically prepared from a starting aromatic compound as shown below.

The desired X and Y groups can be added using methods known to those ofskill in the art, some of which are described below.

Glycolic acid and lactic acid are also known as alpha hydroxy acids(AHA) present in fruits and other foods. These acids are present in manyhealthiest foods we eat and drink, and they are considered to be safewhen used correctly. Glycolic acid occurs naturally as the chief acidicconstituent of sugar cane juice and occurs in beet juice and unripegrapes. Its formula is HOCH₂COOH and is biodegradable. When glycolicacid is heated it readily loses water by self-esterification to formpolyglycolic acid. Glycolic acid can function as both an acid and analcohol. The process of attaching a glycolic acid moiety to the aromaticis defined as glycolation and will be referred to as such in describingthis invention:

Aromatic carboxylic acid can be functionalized with glycolic acid moietyaccording to the following process:

Lactic acid is a fermentation product of lactose. Lactic acid isproduced commercially for use in foods and pharmaceuticals. Manysurgical and orthopedic devices are made from polylactic acid. Theprocess of attaching a lactic acid moiety to the aromatic compound isdefined as lactolation and will be referred to as such in describingthis invention:

ε-Caprolactone is a cyclic monomer and is reactive, and the polymersderived are useful for tailoring specialty polyols andhydroxy-functional polymer resins with enhanced flexibility. The monomerpolymerizes under mild conditions to give low viscosity productssuperior to conventional aliphatic polyesters. Copolymers ofcaprolactone with glycolide and lactide exhibit unique physical andbiological properties as well as different hydrolysis profiles based onthe composition of the monomers. The process of attaching an open chainε-caprolactone moiety to the aromatic compound is defined as caprolationand will be referred to as such in describing this invention:

p-Dioxanone (1,4-dioxan-2-one) is a cyclic monomer and polymers are madevia ring opening polymerization. Polyesters derived from this monomerare used in making absorbable surgical devices with longer absorptionprofile (slower hydrolysis) compare to polyglycolic acid. The absorbablesurgical devices made from 1,4-dioxan-2-one are proved to bebiologically safe, and biocompatible. The process of attaching an openchain p-dioxanone moiety (dioxanone) to the aromatic compound is definedas dioxonation and will be referred to as such in describing thisinvention:

The difunctionalized aromatics of the present invention can be preparedaccording to any recognized method, including the Williamson ethersynthesis.

Williamson Synthesis

Preparation of ethers is an important reaction for which a wide varietyof procedures have been developed during the last 100 years. The mostcommonly used method for the preparation of symmetrical andunsymmetrical ethers is the Williamson synthesis, involving a halide andan alkoxide. It is possible to mix the halide and alcohol with solid KOHand DMSO. The reaction involves an SN2 reaction in which an alkoxide ionreplaces a halogen, sulfonyl, or a sulfate group. Usually, alkyl halidesare used. The alkoxide can be prepared by the reaction of thecorresponding alcohol with an active metal such as metallic sodium or ametal hydride like NaH acting upon the alcohol. The resulting alkoxidesalt is then reacted with the alkyl halide (sulfonate or sulfate) toproduce the ether in an SN2 reaction.

Recently several new procedures for Williamson synthesis have developedin which the phase transfer catalysis (PTC) appear to very convenientand the reactions can be run under mild conditions with high yields.Most recently, it was reported that ethers could be prepared directlyfrom alcohol and alkyl halides under microwave irradiation in thepresence of a quaternary ammonium salt.

For the synthesis of aromatic ethers, the phenolic compound was reactedwith one member of the group Na metal, NaH, and potassium carbonate toform a phenoxide and then reacted with an alkyl halide to form anaromatic ether as shown below:

The first step of the Williamson ether synthesis is the reaction ofsodium hydride with a phenolic compound. Phenols are more acidic thanalkanols because of resonance stabilization of the conjugated anion.

The resulting phenoxide ion is a powerful nucleophile, and reacts wellwith alkyl halide to form an ether.

The alkyl halide should be primary so that the backside attack is notsterically hindered. When it is not primary, elimination usuallyresults.

The general procedure for functionalizing phenolic compounds: to amixture of phenolic compound, anhydrous potassium carbonate, sodiumiodide, and disodium phosphate in anhydrous acetone, while refluxing,the alkyl halide is added and refluxed for a period of from a few hoursto several days until the reaction is essentially complete. Then theacetone is distilled off, water is added, and crude product is filteredand recrystallized from a solvent or mixture of solvents. Some times theproducts are purified by column chromatography. Solvent systems,reaction conditions, and purification methods are modified based on thephenol compound.

The process of preparing a phenolic ester with glycolic acid is shownbelow:

Benzyloxy acetyl chloride (C₆H₅CH₂OCH₂COCl) can be prepared as describedin the following reaction scheme:

Using a similar method, C₆H₅CH₂OCH(CH₃)COCl, C₆H₅CH₂O(CH₂)₅COCl, andC₆H₅CH₂OCH₂CH₂OCH₂COCl were synthesized for preparation of aromaticesters.

Lactic acid can function as both an acid and an alcohol. This dualfunctionality leads to a variety of chemical reactions and valuablephysical properties. The process of preparing a phenolic ester withlactic acid is shown below:

ε-Caprolactone, can function as both an acid and an alcohol. This dualfunctionality leads to a variety of chemical reactions and valuablephysical properties. The process of preparing a phenolic ester withε-caprolactone is shown below:

p-Dioxanone can function as both an acid and an alcohol. This dualfunctionality leads to a variety of chemical reactions and valuablephysical properties. The process of preparing a phenolic ester withp-dioxanone is shown below:

Synthesis of Phenolic amides:

Benzyloxyamides are prepared by reacting benzyloxy acetic acid with anamine using dicyclohexylcarbodiimide (DCC) as coupling agent, indichloromethane (DCM) as a solvent. The amine is dissolved in DCM andbenzyloxyacetic acid is added. While maintaining below room temperature,DCC solution in DCM is added dropwise. The reaction generally proceedscleanly for the formation of an amide. The urea formed is not soluble inDCM, and the urea can be filtered off to get the amide. In a secondmethod the amines are reacted with the acid chloride directly using abase, such as K₂CO₃, NaHCO₃ or triethyl amine to neutralize the HCl thatis formed during the reaction. Acetone is a good solvent for thisreaction. Both methods are suitable for preparing benzyloxyamides.

Synthesis of Phenolic esters:

Conditions similar to those listed above can be used for preparingbenzyloxyesters.

Debenzylation

Debenzylations were done using 50% wet Pd/C (5%) with hydrogen pressureup to 4 kg. MeOH or DMF can be as solvents. Dry Pd/C(5%) can be alsoused to avoid any moisture to avoid ester hydrolysis. DMF, MeOH, orEthyl acetate can be used for this reaction.

SYNTHESIS

The difunctionalized aromatic compounds can be prepared according to anyrecognized method, an example of which is shown below.

Bioactive Formulations

In other aspects of the present invention some difunctionalized aromaticcompounds of the present invention can be further manufactured intoformulations suitable for oral, rectal, parenteral (for example,subcutaneous, intramuscular, intradermal, or intravenous), transdermal,vitreal or topical administration. The most suitable route in any givencase will depend on the nature and severity of the condition beingtreated and on the nature of the particular active compound that isbeing used. The formulations of a pharmaceutical composition aretypically admixed with one or more pharmaceutically or veterinariallyacceptable carriers and/or excipients as are well known in the art.

Formulations suitable for oral administration may be presented indiscrete units, such as capsules, cachets, lozenges, or tablets, eachcontaining a predetermined amount of the active compound; as a powder orgranules; as a solution or a suspension in an aqueous or non-aqueousliquid; or as an oil-in-water or water-in-oil emulsion.

Compositions of the present invention suitable for parenteraladministration conveniently comprise sterile aqueous preparations of theactive compounds, which preparations are preferably isotonic with theblood of the intended recipient.

Formulations suitable for rectal administration are preferably presentedas unit dose suppositories.

Formulations suitable for ocular or vitreal administration may bepresented as bioabsorbable coatings for implantable medical devices,injectables, liquids, gels or suspensions.

Formulations or compositions suitable for topical administration to theskin preferably take the form of an ointment, cream, lotion, paste, gel,spray, aerosol, or oil. Examples of carriers that conventionally usedinclude Vaseline, lanoline, polyethylene glycols, alcohols, andcombination of two or more thereof.

Formulations suitable for transdermal administration may be presented asdiscrete patches adapted to remain in intimate contact with theepidermis of the recipient for a prolonged period of time.

The active compounds may be provided in the form of foodstuffs ornutrition supplements, such as being added to, admixed into, coated,combined or otherwise added to a foodstuff. The term foodstuff is usedin its widest possible sense and includes liquid formulations such asdrinks including dairy products, biodegradable chewing gums, and otherfoods, such as health bars, desserts, etc. Food formulations containingcompounds of the invention can be readily prepared according to standardpractices.

Compounds of the formula used as medicaments or pharmaceuticals aretypically administered in a manner and amount as is conventionallypracticed. See, for example, Goodman and Gilman, The PharmaceuticalBasis of Therapeutics, current edition.

Compounds of the present invention may have potent antioxidant activityand increased acidity of their aromatic component, as well as theimproved biodegradation provided by the functionalization, and thus findwide application in pharmaceutical and veterinary uses, in cosmeticssuch as more effective skin creams to prevent skin ageing, in sunscreens, in foods, health drinks, nutritional supplements, shampoos, andthe like.

Examples of difunctionalized aromatic compounds of the present inventionare provided for some embodiments of the current invention. It can beextended to other species. This selection is not meant to limit thescope of the invention in any way. Other variations in the procedure maybe readily apparent to those skilled in the art.

EXAMPLE 1 Terephthalic Acid Dimethoxycarbonylmethyl Ester

To a mixture of terephthalic acid (210 g, 1.264 mole), anhydrous K₂CO₃(870 g, 6.295 mol) in anhydrous dimethyl formamide (2 L) at 90° C. wasadded methyl chloro acetate (312 g, 2.875 mol) drop wise and maintained90° C. for 16 hours. Reaction mixture was cooled to room temperature andpoured onto ice water (4 liter). The crude material was filtered, washedwith 10% sodium bicarbonate and water, dried, and recrystallized from amixture of chloroform:hexane (1:5) to give the purified title compound(85 g, 21.7%) as a white powder. M.p: 104.5-107° C. ^(I)HNMR (CDCl₃) δ3.82(s, 3H, ester), 4.88 (s, 2H,OCH₂), 8.18 (s,2H,Ar)

EXAMPLE 2 Terephthalic Acid Dimethoxycarbonylmethyl Ester/EthyleneGlycol Polymer

Batch-I Raw material mw Quantity mmoles Example 1 310 10 g 32.25Ethylene glycol 62.07  6 g 96.66 Dibutyl tin oxide 248.92  1 mg 0.004

In to a clean dry 100 mL 4 neck round bottom flask equipped withnitrogen bubbler and distillation condenser were added terephthalic aciddimethoxy carbonyl methyl ester, ethylene glycol and dibutyl tin oxideunder nitrogen atmosphere and heated as described below.

Day-1

Bath 120° C.-4 hours

Bath 140° C.-16 hours

Day-2

Bath 160° C.-23 hours

Heating was cut off and cooled to room temperature

Day-3

High vacuum applied and heating started

Bath 80° C.-3 hours

Bath 90° C.-2 hours

Heating cut off allowed to room temperature, removed vacuum and keptunder nitrogen.

Day-4

High vacuum applied and heating started

Bath 110° C.-1 hour

Bath 120° C.-1 hour

Bath 130° C.-1 hour

Bath 140° C.-1 hour

Heating cut off allowed to room temperature, removed vacuum and keptunder nitrogen

Day-5

High vacuum applied and heating started

Bath 160° C.-7 hours

Heating cut off allowed to room temperature, removed vacuum, sealed theround bottom flask under nitrogen.

Batch-II Raw material mw Quantity mmoles Example 1 310 10 g 32.25Ethylene glycol 62.07 10 g 161.10 Dibutyl tin oxide 248.92  1 mg 0.004

In to a clean dry 100 mL 4 neck round bottomed flask equipped withnitrogen bubbler and distillation condenser were added terephthalic aciddimethoxy carbonyl methyl ester, ethylene glycol and dibutyl tin oxideunder nitrogen atmosphere and heated as described below.

Day-1

Bath 100° C.-4 hours

Bath 120° C.-Over night

Day-2

Bath 120° C.-140° C.-8 hours

Bath 140° C.-Over night

Day-3

Bath 150° C.-1 hour

Bath 160° C.-1 hour

Bath 170° C.-Over night

Day-4

Bath 180° C.-2 hours

Bath 190° C.-1 hour

Heating cut off allowed to room temperature

Day-5

High vacuum applied and heating started

Bath 120° C.-8 hours

Heating cut off allowed to room temperature, removed vacuum and keptunder nitrogen

Day-6

High vacuum applied and heating started

Bath 150° C.-8 hours

Heating cut off allowed to room temperature, removed vacuum and keptunder nitrogen

Day-7

High vacuum applied and heating started

Bath 160° C.-9 hours

Heating cut off allowed to room temperature, removed vacuum and sealedthe round bottom flask under nitrogen.

EXAMPLE 3 2-Benzyloxy-N-[4-(2-benzyloxy-acetylamino)-phenyl]-acetamide

To a mixture of 1,4-phenylenediamine (10 grams, 92.47 mmol), sodiumbicarbonate (15.46 grams, 184.07 mmol) in ethyl acetate (100 mL) at 0°C. is added benzyloxy acetyl chloride (23.19 grams, 125.71 mmol) dropwise. The reaction mixture is stirred at room temperature for 10 hours.The solids are filtered, and the ethyl acetate layer is washed with 5%sodium bicarbonate solution (2×25 mL), water (2×25 mL), dried oversodium sulfate, and distilled to get crude 3, which can be purified bysuitable solvent.

EXAMPLE 4 2-Hydroxy-N-[4-(2-hydroxy-acetylamino)-phenyl]-acetamide

2-Benzyloxy-N-[4-(2-benzyloxy-acetylamino)-phenyl]-acetamide 3 (10grams, 24.75 mmol) is dissolved in methanol (100 mL) in a pressurevessel. Pd/C (10%, 3 grams) is added, and the mixture is stirred underan atmosphere of hydrogen (4 Kg) for 5 hours. The catalyst is removed byfiltration, and the methanol is distilled off. The crude 4 can bepurified in a suitable solvent.

EXAMPLE 5 4-Nitro-benzoic acid methoxycarbonylmethyl ester

To mixture of 4-nitro benzoic acid (30 grams, 180 mmol) andtriethylamine (45.5 grams, 450 mmol) in acetone (300 mL) was addedmethyl chloro acetate (29 grams, 267 mmol) drop wise, which was stirredunder reflux for 20 hours. The solids were filtered off and the acetonedistilled to give crude 5. Crude 5 was purified by column chromatographyon silica gel using benzene as eluant to get pure 5 (16 grams, 37.3%) asa light yellow powder. M.p: 69-70.5° C. ^(I)H NMR (CDCl₃)δ3.80(s,3H,ester), 4.86(s,2H,CH₂), 8.26(dd,4H,Ar).

EXAMPLE 6 4-Amino-benzoic acid methoxycarbonylmethyl ester

4-Nitro-benzoic acid methoxycarbonylmethyl ester 5 (15 grams, 62.76mmol) was dissolved in methanol (150 mL) in a pressure vessel. Raneynickel (10 grams) was added, and the mixture stirred under an atmosphereof hydrogen (4 Kg) for 5 hours. The catalyst was removed by filtrationand the methanol distilled off. The crude 6 was purified by columnchromatography on silica gel using chloroform as eluant to get pure 6 (3grams, 22.9%) as a white powder. M.p: 116-118° C. ^(I)H NMR (CDCl₃)δ3.78(s,3H,ester), 4.15(bs,2H,NH₂), 4.80(s,2H,CH₂), 6.60(d,2H,Ar),7.90(d,2H,Ar).

EXAMPLE 7 4-(2-Benzyloxy-acetylamino)-benzoic acid methoxycarbonylmethylester

To a mixture of 4-amino-benzoic acid methoxycarbonylmethyl ester 6 (10grams, 47.84 mmol) and sodium bicarbonate (8 grams, 95.23 mmol) in ethylacetate (50 mL) at 0° C. is added benzyloxy acetyl chloride (12 grams,65.04 mmol) drop wise. The reaction mixture is stirred at roomtemperature for 10 hours. The solids are filtered off, and the ethylacetate layer is washed with 5% sodium bicarbonate solution (2×25 mL),water (2×25 mL), dried over sodium sulfate, and distilled to give crude7, which can be purified via crystallized with a suitable solvent.

EXAMPLE 8 4-(2-Hydroxy-acetylamino)-benzoic acid methoxycarbonylmethylester

4-(2-Benzyloxy-acetylamino)-benzoic acid methoxycarbonylmethyl ester 7(10 grams, 28.98 mmol) is dissolved in methanol (100 mL) in a pressurevessel. Pd/C (10%, 3 grams) is added, and the mixture is stirred underan atmosphere of hydrogen (4 Kg) for 5 hours. The catalyst is removed byfiltration, and the methanol is distilled off. The crude 8 can bepurified in a suitable solvent.

EXAMPLE 9 4-Isocyanato-benzoic acid methoxycarbonylmethyl ester

To a mixture of 4-amino-benzoic acid methoxycarbonylmethyl ester 6 (10grams, 47.84 mmol) and triethylamine (9.68 grams, 95.67 mmol) in toluene(150 mL) under nitrogen atmosphere at 0° C. is added triphosgene (5.195grams, 17.50 mmol) in one lot. Later the reaction mixture is heated to75° C. over a period of one hour and maintained at this temperature for20 hours. The reaction mixture is cooled to room temperature. The solidsare filtered off, and the toluene is distilled under vacuum to givecrude 11, which can be purified by a suitable method.

EXAMPLE 10 4-(2-Hydroxy-ethoxycarbonylamino)-benzoic acidmethoxycarbonylmethyl ester

4-Isocyanato-benzoic acid methoxycarbonylmethyl ester 9 (5 grams, 21.09mmol) is added to ethylene glycol (20 mL) at room temperature andstirred for 6 hours. Water (100 mL) is added, and crude 10 is filtered,dried, and purified by a suitable method.

EXAMPLE 11 4-Amino-benzoic acid methyl ester

To a solution of 4-amino benzoic acid (100 grams, 729.18 mmol) inmethanol (1000 mL) at 0° C. is passed dry HCl for 3 hours. The solutionis then refluxed for 10 hours. Excess methanol is distilled, and water(1000 mL) is added. The solution is neutralized with dilute ammonia,filtered, and purified from an appropriate solvent.

EXAMPLE 12 4-(2-Benzyloxy-acetylamino)-benzoic acid methyl ester

To a mixture of 4-amino-benzoic acid methyl ester 11 (10 grams, 66.15mmol) and sodium bicarbonate (11 grams, 131.67 mmol) in ethyl acetate(150 mL) at 0° C. is added benzyloxy acetyl chloride (16.6 grams, 89.93mmol) drop wise. The reaction mixture is stirred at room temperature for10 hours. The solids are filtered off. The ethyl acetate layer is washedwith 5% sodium bicarbonate solution (2×25 mL), water (2×25 mL), driedover sodium sulfate, and distilled to get crude 12, which can bepurified in a suitable solvent.

EXAMPLE 13 4-(2-Hydroxy-acetylamino)-benzoic acid methyl ester

4-(2-benzyloxy-acetylamino)-benzoic acid methyl ester 12 (10 grams,33.44 mmol) is dissolved in methanol (100 mL) in a pressure vessel. Pd/C(10%, 3 grams) is added, and the mixture is stirred under an atmosphereof hydrogen (4 Kg) for 5 hours. The catalyst is removed by filtrationand the methanol distilled off. The crude 13 can be purified in asuitable solvent.

IN VITRO HYDROLYSIS OF FUNCTIONALIZED AROMATICS

A compound and a polymer of the present invention were examined fortheir rates of hydrolysis as described below.

EXAMPLE 14 4-Methoxycarbonylmethoxycarbonylmethoxy-benzoic acidmethoxycarbonyl methyl ester

Compound: 100 mg

Aldrich pH 7.4 buffer: 10 mL

Temperature: 100° C.

Method: Monitoring by TLC for disappearance of starting material

Hydrolyzed in 26.5 hours

Compound: 100 mg

Aldrich pH 9 buffer: 10 mL

Dilution: 1% solution

Temperature: 100° C.

Method: Monitoring by TLC for disappearance of starting material

Hydrolyzed in 5 hours

EXAMPLE 15

Polymer: 100 mg

Aldrich pH 7.4 buffer: 10 mL

Temperature: 100° C.

Method: Monitoring by TLC for disappearance of starting material

Hydrolyzed in 50-60% in 118 hours

Polymer: 100 mg

Aldrich pH 4 buffer: 10 mL

Temperature: 100° C.

Method: Monitoring by TLC for disappearance of starting material

Hydrolyzed in 50% in 17 hours

Polymer: 100 mg

Aldrich pH 9 buffer: 10 mL

Temperature: 100° C.

Method: Monitoring by TLC for disappearance of starting material

Hydrolyzed in 70% in 13 hours

The above hydrolysis examples indicate that the difunctionalizedaromatic compounds of the present invention hydrolyze and also thatpolymers derived from the difunctionalized aromatic compounds hydrolyze.Therefore, using the difunctionalized aromatic compounds, it is expectthat one can develop polymers with controlled hydrolysis profiles.

1. A compound of formula I or a pharmaceutically acceptable saltthereof:[R′—(X)_(a)—OC(O)]_(p)—Ar—[NR′—(Y)_(b)—R′]_(q)  I wherein: Ar is anaromatic ring substituted with 1, 2, or 3 R groups; X is independentlyat each occurrence selected from: —CH₂COO—; —CH(CH₃)COO—;—CH₂CH₂OCH₂COO—; —CH₂CH₂CH₂CH₂CH₂CO O—; —(CH₂)_(y)COO—; and,—(CH₂CH₂O)_(z)CH₂COO—, where y is independently selected from 2,3,4 and6-24 and z is independently selected from 2-24; Y is independently ateach occurrence selected from: —COCH₂O—; —COCH(CH₃)O—; —COCH₂OCH₂CH₂O—;—COCH₂CH₂CH₂CH₂CH₂ O—; —CO(CH₂)_(m)O—; and, —COCH₂O(CH₂CH₂O)_(n)—, wherem is selected from 2-4 and 6-24 and n is selected from 2-24; R′ isselected from hydrogen, benzyl, and C₁₋₆ alkyl; p and q areindependently selected from 0, 1, 2, 3, and 4, provided that p+q total2, 3, or 4; a and b, are independently selected from 0, 1, 2, 3, and 4,provided that a+b total from 1, 2, 3, 4, 5, or 6; R is independentlyselected from —O—(X)_(c)—R′ and —O—(Y)_(c)—R′; c is independentlyselected from 0, 1, 2, 3, and 4; alternatively, R is independentlyselected from H, ═O, O-glycosides, —(CH₂)₀₋₂—OR^(a), —(CH₂)₀₋₂—C₆H₅,—(CH₂)₀₋₂—CHO, Cl, F, Br, I, —(CH₂)₀₋₂—OC(O)—R^(a), —(CH₂)₀₋₂—CO₂—R^(a),—(C(CH₃))₀₋₂—CO₂—R^(a), —(CH₂)₁₋₂—CO₂—(CH₂)₁₋₂ 13 CO₂—R²,—(C(CH₃))₁₋₂—CO₂—(CH₂)₁₋₂—CO₂—R^(a), —(CH₂)₀₋₂—CO—R^(a),—O(CH₂)₀₋₂—C₆H₅, —O(₂—CO₂R², —O(C(CH₃))₁₋₂—CO₂—R^(a),—O(CH₂)₁₋₂—CO—R^(a), —(CH₂)₀₋₂—NO₂, —(CH₂)₀₋₂—NR^(a)R^(a),—(CH₂)₀₋₂—NR^(a)COR^(a), —(CH₂)₁₋₂—NR^(a)C(O)(CH₂)₁₋₂OR^(a), —C₆H₅,—C₆H₅OR^(a), and —C₆H₅—CH═CHCO₂R^(a); and, R^(a) is independentlyselected from H and C₁₋₆ alkyl.
 2. A compound according to claim 1,wherein X is independently at each occurrence selected from: —CH₂COO—;—CH(CH₃)COO—; —CH₂CH₂OCH₂COO—; and, —CH₂CH₂CH₂CH₂CH₂COO—; Y isindependently at each occurrence selected from: —COCH₂O—; —COCH(CH₃)O—;—COCH₂OCH₂ CH₂O—; —COCH₂CH₂CH₂CH₂CH₂O—; p and q are independentlyselected from 0, 1, 2, and 3, provided that p+q total 2 or 3; a and b,are independently selected from 0, 1, 2, and 3, provided that a+b totalfrom 1, 2, 3, or 4; and, c is independently selected from 0, 1, 2, and3.
 3. A compound according to claim 2, wherein X is independently ateach occurrence selected from: —CH₂COO— and —CH(CH₃)COO—; Y isindependently at each occurrence selected from: —COCH₂O— and—COCH(CH₃)O—; a and b, are independently selected from 0, 1, and 2,provided that a+b total from 1, 2, 3, or 4; and, c is independentlyselected from 0, 1, and
 2. 4. A compound according to claim 2, wherein:Ar is an aromatic ring substituted with 1, 2, or 3 R groups and thearomatic ring consists of 1-6 phenyl rings.
 5. A compound according toclaim 2, wherein: Ar is an aromatic ring substituted with 1, 2, or 3 Rgroups and the aromatic ring consists of 1-3 phenyl rings.
 6. A compoundaccording to claim 2, wherein: Ar is selected from phenyl and naphthyland is substituted with 1, 2, or 3 R.
 7. A compound according to claim1, wherein the compound is of formula Ia-Ic:


8. A compound according to claim 1, wherein the compound is of formulaIIa-IIc:


9. A compound according to claim 1, wherein the compound is of formulaIIIa IIIc:


10. A compound according to claim 1, wherein the compound is selectedfrom:


11. A composition, comprising: at least two different compounds of claim2.
 12. A solvent for a drug, comprising: at least one compound of claim2.
 13. A cosmetic composition, comprising at least one compound of claim2 and a cosmetic ingredient.
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